The present invention relates to tetramides which are derived from the pair of RRRR/SSSS enantiomers of tetra(xcex1-carboxyethyl)gadoterate, represented by the formulae 
It is disclosed in EP 0 661 279 that the amides of formula II 
in which R is a bulky hydrophilic group with a molecular mass or greater than 200, exhibit a longitudinal relativity r1 which is markedly superior to those of the chelates not carrying the bulky side group (CH2)2CONHR and can be used as contrast agents in magnetic resonance diagnostic imaging.
WO 97/01359 relates to the products of formula II in which R is a group of formula 
Application EP 98 403108 of Dec. 9, 1998 relates to the products of formula II in which R is the following group 
It is known that the relaxivity r1 of a gadolinium chelate is a complex function of various more or less independent factors, including the electronic correlation time, rotation correlation time and water exchange time, which factors depend in particular on the spatial structure of the chelating agent around the paramagnetic cation, so that 2 stereoisomers can have substantially different relaxivities.
Furthermore, it is essential for the specific characteristics of a pharmaceutical product to be reproducible in terms of effectiveness and of toxicity between successive manufacturing batches and it can be difficult to ensure such reproducibility in the presence of numerous stereoisomers because of their substantial differences in chemical reactivity and in physical properties.
It was thus desirable to find a process which makes it possible, at the industrial stage under acceptable economic conditions, to obtain a mixture of stereoisomers of the amides of formula II in exactly defined proportions and thus to isolate, with good yields, one of the possible racemic compounds which does not comprise the other stereoisomers and which exhibits an advantageous relaxivity r1 in the range of the fields currently used clinically, namely between 0.5 and 1.5 tesla.
The racemic compounds according to the invention are represented by the formula III 
in which R is a phenyl group or (C1-C8) alkyl group which are substituted or interrupted by one or more groups selected from phenyl, alkyl, oxy, amino or amido groups, which may or may not be substituted by alkyl, it being possible for the phenyl groups to be substituted by OH, Br, Cl, I, (C1-C8)alkyl, (C1-C8)alkyleneoxy, NO2; NRxRy, NRxCORy, CONRxRy or COORx, Rx and Ry being (C1-C8)alkyl or H,
and it being possible for the linear or branched or cyclic alkyl groups to be hydroxylated,
and the salts of these acids with inorganic or organic bases, such as NaOH, KOH, N-methylglucamine, tris-(hydroxymethyl)aminomethane, lysine or diethanolamine.
Preference is given, among these, to the compounds in which
R is a group of formula 
xe2x80x83in which X is Br or I, R1 is H, (C1-C3)alkyl or (C2-C8)mono- or polyhydroxyalkyl and R2 is (C2-C8)mono- or polyhydroxyalkyl, or else R1 is H and R2 is a group of formula 
X being as defined above and Rxe2x80x21 and Rxe2x80x22 taking any one of the meanings given for R1 and R2, with the exception of A, it being understood that xe2x80x94COxe2x80x94NR1R2 or xe2x80x94COxe2x80x94NRxe2x80x21Rxe2x80x22 comprise at least two hydroxyl groups, and those in which R is a group 
in which a is 1 or 2,
Z is a bond, CH2, CH2CONH or (CH2)2NHCO,
Zxe2x80x2 is a bond, O, S, NQ, CH2, CO, COxe2x80x94NQ, NQxe2x80x94CO, NQxe2x80x94COxe2x80x94NQ or COxe2x80x94NQxe2x80x94CH2xe2x80x94CONQ,
Zxe2x80x3 is COxe2x80x94NQ, NQxe2x80x94CO, COxe2x80x94NQxe2x80x94CH2xe2x80x94COxe2x80x94NQ or NQxe2x80x94COxe2x80x94CH2xe2x80x94NQxe2x80x94CQ, with Q being H or an optionally hydroxylated (C1-C4) alkyl group,
R1, R2, R3, R4 and R5, independently of one another, are selected from H, Br, Cl, I, COxe2x80x94NQ1Q2 or N(Q1)xe2x80x94COxe2x80x94Q2, and Q1 and Q2, which are identical or different, are selected from optionally hydroxylated (C2-C6) alkyl groups optionally interrupted by an oxygen atom, so that Q1 and Q2 together comprise from 4 to 10 OH groups, it being understood that at least 1 and at most 2 R1, R2, R3, R4 and R5 groups are amide groups.
The racemic compounds of the invention can be prepared by a method known per se by reaction of the amine RNH2 with the pair of complexes of the enantiomeric octaacids of formula I in aqueous solution with an agent which activates carboxyl functional groups under conventional conditions for peptide condensations, as disclosed in the abovementioned patents, for mixtures of isomers.
Some of the isomers of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(2-glutaric acid), obtained by hydrolysis of the corresponding ethyl esters, separated by silica liquid chromatography and crystallization from water, have been described by Judith A. K. Howard et al. in Chem. Commun., 1381-1382 (1998).
A process which can be operated industrially has now been found which makes it possible to obtain the pair of RRRR/SSSS enantiomers starting from the mixture of the stereoisomers of the gadolinium complex of this octaacid resulting from the substitution, by a conventional method, of the nitrogen atoms of 1,4,7,10-tetraazacycladodecane. It consists in carrying out the isoomerization by simple heating in aqueous solution at acidic pH, preferably between 2 and 4.5 and better still between 2.5 and 3.5, and at a temperature of greater than 70xc2x0 C., preferably of greater than 90xc2x0 C. and better still at reflux of the solution, for the time needed to obtain the racemic compound of the invention, i.e. from a few hours to a few days, in particular 35 to 45 hours at reflux at approximately pH 3.
The starting mixture of the stereoisomers can be obtained by the action of the compound of formula Rxe2x80x2OOCxe2x80x94CHXxe2x80x94(CH2)2xe2x80x94COORxe2x80x2, in which Rxe2x80x2=H or (C1-C3)alkyl and X is a leaving group in a nucleophilic substitution, in particular a halogen atom, preferably bromine, or a sulphonate or tosylate or triflate group, which reaction is followed by the hydrolysis of the ester functional groups, in particular by the action of an alkaline carbonate or hydroxide in an alcoholic, agueous/alcoholic or aqueous medium.
A person skilled in the art will select, during preliminary trials, the concentration of the solution, the pH, the temperature and the duration of the heating in order to carry out complete isomerization without significant decomposition, in particular according to the product and the amount treated.
It is surprising that, under these conditions, the chelate is not decomplexed and that the decomposition of the ligand is negligible and that, in addition, the pair of enantiomers which is finally isolated comprise less than 15% of the 3 pairs formed on conclusion of a conventional synthesis, which consists in hydrolysing, in basic medium, the product obtained by reaction of ethyl 2-bromoglutarate with the heterocycle and in then carrying out its complexation by the action of GdCl3 or to Gd2O3.
Thus, according to another of its aspects, the present invention relates to a process comprising the stages consisting:
1xe2x80x94in keeping an aqueous solution of the mixture of the stereoisomers of the gadolinium complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(2-glutaric acid), with a pH of between 2 and 4.5, at a temperature of greater than 70xc2x0 C. for a few hours to a few days, so as to obtain the racemic mixture of octaacids of formula: 
2xe2x80x94in reacting this mixture with the amine RNH2, R being defined above for the Formula III, with an agent which activates the acid functional group.
The starting mixture of the stereoisomers of the gadolinium complex of 1,4,7,10-tetraazacyclododecane-4,7,10-tetra(2-glutaric acid) of formula; 
can be obtained in a simple fashion by employing a process comprising the stages consisting in:
reacting 1,4,7,10-tetraazacyclododecane with a compound of formula Rxe2x80x2OOCxe2x80x94CHX(CH2)2xe2x80x94COORxe2x80x2 in which Rxe2x80x2 is a hydrogen atom or (C1-C3)alkyl and X is a leaving is group;
conventionally hydrolysing the ester functional group of the resulting compound when Rxe2x80x2 is other than H; and
complexing the compound thus obtained with the gadolinium ion.
Mention may be made, as leaving group which can be used, of the sulphonate, tosylate and triflate groups.
The invention also relates to compositions for nuclear magnetic resonance medical imaging which comprise the racemic compounds of the invention in combination with conventional vehicles and additives. The doses at which these contrast agents will be administered depend on their magnetic efficiency, on their biodistribution and on their administration route, as on the size of the subject, on the organ to be observed and on the nature of the pathology. For an intravascular administration, the unit concentration will be between 0.5 and 5 mM for an adult, presented in aqueous solution.
In that which follows, examples of the preparation of the compounds of the invention are described.
The isolated products are characterized by their retention times (tr) in high performance liquid chromatography (HPLC). Their molecular masses were determined by mass spectrometry (electrospray).